2'-DEOXYCYTIDINE KINASE-DEFICIENCY IS A MAJOR DETERMINANT OF 2-CHLORO-2'-DEOXYADENOSINE RESISTANCE IN LYMPHOID-CELL LINES

2-Chloro-2'-deoxyadenosine, (CldAdo) resistance was developed in the W 1L2 human B lymphoblastoid (resistance factor, 160) and L1210 murine l eukemia (resistance factor, 605) cell lines by continuous exposure to CldAdo. Cross-resistance studies showed that while the variant lines g enerally retained sensitivities to 9-beta-D-arabinofuranosyladenine (i n the presence of 2'-deoxycoformycin), hydroxyurea, and Adriamycin, bo th were highly cross-resistant to 1-beta-D-arabinofuranosylcytosine (a ra-C), 2',2'-difluorodeoxycytidine, and 9-beta-D-arabinofuranosyl-2-fl uoroadenine. Measurement of both phosphorylating and degrading enzyme activities demonstrated that initial phosphorylation of CldAdo and 2'- deoxycytidine were severely impaired in cell extracts from the resista nt lines, whereas adenosine kinase activity remained unaffected and th ere was no apparent increase in cytoplasmic deoxynucleotidase activity using dCMP as substrate. Since previous reports indicated that either overexpression of Bcl-2 protein following bcl-2 transfection into cel ls resulted in, or high dCTP pools contributed to, ara-C resistance in experimental cell models, both of these parameters were assessed and found not to contribute to CldAdo resistance in the murine leukemia an d human B lymphoblastoid cells. These studies show that a deficiency o f 2'-deoxycytidine kinase activity is a major determinant of CldAdo ac quired resistance in both the murine and human lymphoid lines.